Approaches to therapeutic intervention for food allergies include the prevention of food allergy and the treatment with immunotherapy for an individual with an established allergy [1]. In this proposal, both of these interventions will be developed for cashew allergy. Our preliminary data indicate that pepsin digested cashew proteins can proliferate splenocytes from cashew-sensitized mice, inducing a Th1-skewed cytokine response relative to native cashew proteins, and are significantly less allergenic on in vivo challenge of cashew-sensitized mice. The goals of this proposal are to: (1) develop pepsin digestion fragments of cashew allergy as a tolerizing vaccine such that exposure to native cashew allergens will not cause hypersensitivity in predisposed animals and (2) to develop these pepsinized cashew proteins as a novel approach to specific-immunotherapy for cashew allergy. Pepsinized cashew proteins will be tested as a prophylactic approach to prevent cashew allergy by administering tolerizing doses prior to an established sensitizing protocol in the C3H/HeJ-cholera toxin model [2] as well as our novel model of food allergy in DGK-zeta knockout mice. Our hypothesis is that tolerization with pepsinized cashew proteins will drive the T cell response towards a protective Th1 and/or Treg phenotype [3], preventing subsequent allergic sensitization to native cashew proteins. Immunotherapy using pepsinized cashew proteins for established cashew hypersensitivity will also be tested in these two mouse models with the hypothesis that pepsin digested protein immunotherapy will have less side-effects and will be efficient in modulating the Th2 phenotype [4]. Effectiveness at both prevention and treatment of cashew allergy will be assessed by allergic reactions to cashew challenge, humoral response, and T cell responses [5]. The completion of these studies will help to better understand the mechanisms of the development of food allergy by the prevention studies and of allergen immunotherapy by the therapeutic studies. Food allergies are a serious public health concern because of the life-threatening anaphylactic reactions often associated with allergies to foods such as tree nuts and peanuts. The proposed research aims to develop a preventative vaccine for cashew allergy, as well as a treatment option for established cashew allergy. These studies will provide an understanding of why the immune system develops an allergy to harmless food proteins and how the immune system changes during treatment of a food allergy.